Abstract 10290: αB-crystallin Knockout Alleviate Tsc1 Deletion Induced Cardiomyopathy

Introduction: Mechanistic target of rapamycin (mTOR) signaling is important in many diseases, such as cancer, metabolic diseases and cardiac diseases. Inactive mutation of either TSC1 or TSC2 leads to activation of mTOR. We recently reported that cardiomyocyte-specific TSC1 deficiency induced cardiomyopathy and impaired cardiac function in mice. A ubiquitous small heat-shock protein (sHSP), αB-crystallin as a downstream target protein of mTOR signaling pathway is one of the central controllers of cell growth, proliferation and cancer development. Hypothesis: Hyper-activation of mTOR induces cardiac hypertrophy through upregulation of αB-crystallin and inhibition of αB-crystallin may abolish mTOR activation-induced cardiomyopathy. Methods: Cardiomyocyte-specific Tsc1 knockout ( Tsc1 -cKO) mice were mated with αB-crystallin knockout ( αB -KO) mice to create Tsc1 and αB-crystallin double knockout (dKO) mice. Tamoxifen(TMX) was used to induce cardiomyocyte-specific Tsc1 knockout. Analysis of morphology, cardiac function and fetal gene expression were performed in different genotypes of mice. Results: Tsc1 -cKO mice showed higher heart weight/body weight (HW/BW) ratio, thinner ventricular walls and larger cardiac chambers, nevertheless all of these changes significantly alleviated in the dKO mice(Figure A and B). Cardiac function detected by echocardiography impaired in the Tsc1 -cKO mice, while dKO mice showed no different with the control littermates (Figure C). The mRNA expression of fetal genes including α-skeletal actin (α-SKA), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) elevated significantly in the Tsc1 -cKO mice, however, the expression of these genes in the dKO mice was the same as the control mice(Figure D). Conclusions: The present study indicates that αB-crystallin plays a critical role in TSC1 deficiency induced cardiomyopathy.